MHC class II (MHC II) molecules associate with a chaperone protein termed the Invariant chain (Ii) that facilitates the transport of newly synthesized MHC-II to endo/lysosomal antigen processing compartments. Expression of Ii is required for APCs to stimulate most, but not all, antigen-specific T cells. It is thought that these Ii-independent antigens are presented by pre-existing peptide-loaded MHC-II (pMHC-II) that internalize from the plasma membrane, enter into endosomal compartments, exchange old peptides for new antigenic peptides, and then recycle back to the plasma membrane for presentation to CD4 T cells. Unlike Ii-associated MHC-II, pre-existing pMHC-II on the plasma membrane rapidly internalizes into APCs and is returned to the plasma membrane following an Arf6, Rab35, and EHD1-dependent recycling pathway. We have found that the recycling of MHC-II is inhibited by ubiquitination by the March-I E3 ubiquitin ligase in immature DCs and B cells and we are following up on this observation by attempting to regulate MHC-II recycling in a variety of APC types to examine the importance of this post-translational modification on MHC-II function.MHC-II molecules bind antigenic peptides derived from internalized protein antigens, and any defect in antigen internalization can adversely affect the ability of APCs to function as stimulators of immunity.